New NO-donors with antithrombotic and vasodilating activities, Part 17. Arylazoamidoximes and 3-arylazo-1,2,4-oxadiazol-5-ones.
Seven arylazoamidoximes (3), six phenoxycarbonyl derivatives (4), and six 1,2,4-oxadiazol-5-ones (5) have been prepared and their structure and purity established by spectroscopy and elemental analysis. In the EI mass spectra ready elimination of NO from the title amidoximes was observed. A new addition reaction of 3a with hydrochloric acid to 4-chlorophenylhydro-azoamidoxime 7 is described. The compounds were tested for nitric oxide dependent biological properties, i.e. platelet aggregation, antithrombotic effects, and decrease in blood pressure. In arterioles of rats 5/19 compounds inhibited the formation of thrombi with a laser beam by > or = 20% 2 h after oral administration of 60 mg/kg. Among these are three amidoximes (3a, 3e, 3f), one phenoxycarbonyl derivative (4a), and one oxadiazolone (5a). With the 4-chlorophenylazoamidoxime 3c a long lasting (24 h) decrease of blood pressure in spontaneously hypertensive rats was observed. Microsomal fractions of rat liver oxidize arylazoamidoximes and generate nitric oxide (e.g. 3a and 3b). NO was measured by the oxyhemoglobin assay. The influence of SOD, pretreatment of the rats with dexamethasone, as well as kinetic parameters were determined. Type 3 compounds, therefore, are a new class of NO donors. Type 4 and 5 compounds function as their prodrugs.
Rehse
K
K
Institut für Pharmazie I, Freie Universität Berlin, Germany.
Bade
S
S
Harsdorf
A
A
Clement
B
B
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D009569:Nitric Oxide / Q000096:biosynthesis*; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D010091:Oximes / Q000138:chemical synthesis / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000494:pharmacology; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000494:pharmacology*
D005343:Fibrinolytic Agents; D010069:Oxadiazoles; D010091:Oximes; D010975:Platelet Aggregation Inhibitors; D014665:Vasodilator Agents; D009569:Nitric Oxide; D013482:Superoxide Dismutase